The overall objective of this proposal is to continue and extend studies of metabolism, distribution, excretion and persistence of long-acting narcotics using methadone as a prototypic agent both in tolerant humans maintained on methadone, and in naive and tolerant animals. Studies will be carried out in the setting of normal and altered physiological states. Studies will be performed in healthy subjects on chronic methadone maintenance treatment and in maintenance patients with chronic liver disease of varying types and degrees of severity. Drug interactions between methadone and agents which may alter its metabolism disposition and which are commonly abused or medically used including barbiturates, estrogens, ethanol, diazepam, amitriptyline, phenytoin and rifampin will be studied. Findings will be related to observed physiological effects in each of these settings. Studies on the possible role of the intestine in biotransformations of long-acting narcotics are to be performed. Studies of the biliary secretion and enterohepatic circulation of methadone and its metabolites in man will be carried out. Stable isotope technology will be used with pentadeuteromethadone and octadeuteromethadone as tracers and measurements made by quadrupole chemical ionization mass spectrometry. Radioisotope studies utilizing tissue oxidation and scintillation counting and balance studies with quantitative and qualitative analyses using gas, high pressure liquid, and thin layer chromatography and mass spectrometry will be carried out. Breath tests to measure rates of N-demethylation of narcotics will be developed.